β-cell dedifferentiation in diabetes is important, but what is it?

Abstract

This commentary discusses the concept of β-cell dedifferentiation in diabetes, which is important but not well defined. A broad interpretation is that a state of differentiation has been lost, which means changes in gene expression as well as in structural and functional elements. Thus, a fully mature healthy β cell will have its unique differentiation characteristics, but maturing cells and old β cells will have different patterns of gene expression and might therefore be considered as dedifferentiated. The meaning of dedifferentiation is now being debated because β cells in the diabetic state lose components of their differentiated state, which results in severe dysfunction of insulin secretion. The major cause of this change is thought to be glucose toxicity (glucotoxicity) and that lowering glucose levels with treatment results in some restoration of function. An issue to be discussed is whether dedifferentiated β cells return to a multipotent precursor cell phenotype or whether they follow a different pathway of dedifferentiation.

Growth factors and medium hyperglycemia induce Sox9+ductal cell differentiation into β cells in mice with reversal of diabetes

“…This condition appears to be strict, because a combination of high hyperglycemia and long-term administration of GE did not work. This result may be due to the glucose toxicity to newly generated β cells, as previously reported (19,20). The combination of medium hyperglycemia and short-term administration of GE did not effectively augment Sox9 + ductal cell differentiation either, although the treatment effectively augmented the replication of preexisting β cells.…”

“…Chronic hyperglycemia is also toxic to β cells and causes their dysfunction and dedifferentiation (19,20). However, the impact of hyperglycemia on β-cell neogenesis remains unclear.…”

“…These reports suggest that PDL injury with normal glycemia, hyperglycemia alone, or hyperglycemia plus short-term (1 wk) administration of GE is not able to augment pancreatic Sox9 + ductal cell differentiation into insulin-producing β cells in adult mice. Actually, how hyperglycemia regulates progenitor differentiation into β cells remains largely unknown, although it has been reported that hyperglycemia is toxic to β cells (19,20).…”

Anti-diabetic action of all-trans retinoic acid and the orphan G protein coupled receptor GPRC5C in pancreatic β-cells

“…Additional evidence for an important role of GPRC5C in β-cell expansion is provided by the observation that Gprc5c is more abundantly expressed in pancreatic islets of newborn mice (<3 weeks old) compared to older (>46 weeks) mice. It is known that rodent β-cells in fetal and neonatal islets are not fully developed and continue to differentiate into functional β-cells almost up to 4 weeks after birth [5,25]. Since Gprc5c is highly expressed during the fetal/neonatal stage and it is known to play an important role in embryogenesis [14,23,26], it seems likely that Gprc5c influences cell proliferation and thereby contributes to the appropriate expansion and maintenance of functional β-cell mass.…”

“…To investigate the effects of GPRC5C down-regulation on β-cell proliferation, we used mouse Min6c4 insulinoma cells rather than primary mouse β-cells as the latter exhibit a low rate of cell division [5]. As shown in Fig.…”